6-azaestranes, intermediates and process



United States Patent 3,328,408 -AZAESTRANES, INTERMEDIATES AND PROCESSGordon Alan Hughes, Wayne, Pa., and Herchel Smith,

500 Chestnut Lane, Wayne, Pa. 19087; said Hughes assignor to said SmithFiled Jan. 30, 1964, Ser. No. 341,345 4 Claims. (Ci. 260283) Thisapplication is a continuation-in-part of co-pending application Ser. No.228,384, filed Oct. 4, 1962, which is a continuation of applicationsSer. No. 57,904, filed Sept. 23, 1960; Ser. No. 91,341, filed Feb. 24,1961; Ser. No. 137,535, filed Sept. 12, 1961; Ser. No. 195,000, filedMay 15, 1962; and ser. No. 196,557, filed May 16, 1962, all of whichlatter applications have been abandoned.

The invention relates to compositions of matter classified in the art ofchemistry as estranes, more particularly to 6-azaestranes, tointermediates therefor, and to processes for making and using suchcompositions.

The term estrane, as used by chemists, refers to the tetracyclicperhydrocyclopent-anophenanthrene nucleus, having a methyl group at the13-position thereof. The compositions of this invention possess anitrogen atom in place of the carbon atom at position 6 of the estranenucleus and hence are designated 6-azaestranes. In the normalconfiguration of the estrane system, any hydrogen atoms appearing at the8, 10, and 13-positions possess what is designated as thefl-configuration, i.e. they extend in a direction above the averageplane of the tetracyclic ring system; and hydrogens present at the 9 and14-positions, possess what is designated as the rat-configuration, i.e.they extend in a direction below the plane of the ring system. While thecompositions of the invention are named to describe the stereochemicalconfiguration corresponding to that of the normal estranes, it is to beunderstood that the product of each of the given reactions is a racemicmixture of the named compound and its enantiomorph.

In describing the invention, reference will be made in the followingspecification to the annexed drawing, wherein:

FIGURE 1 illustrates schematically the reaction sequence for preparing a6-azaestra-1,3,5 l0),8.14-pentaene, specifically 3 methoxy 6phenylsulfonyl 6 azaestra- 1,3,5(),8,14-pentaen-l7-one.

FIGURE 2 illustrates schematically the reaction sequence for preparing a6-azaestra-1,3,5(10),6,8-pentaene, specifically3-methoxy-6-azaestra-1,3,5 (10),6,8 pentaen- 17-01.

The invention sought to be patented in a principal composition aspect isdescribed as residing in the concept of a chemical compound having a3-methoxy 6 azaestra- 1,3,5(10),8,14-pentaen-17-one structure.

The tangible embodiments of the composition aspects of the inventionpossess the inherent general physical propertie of being whitecrystalline solids, are substantially insoluble in water and aregenerally soluble in organic solvents such benzene and tetrahydrofuran.Examination of the compounds produced according to the hereinafterdescribed process reveals, upon ultraviolet and infrared spectrographicanalyses, spectral data supporting the molecular structures herein setforth. Particularly evident are spectral characteristics indicative ofthe 6-nitrogen atom. The aforementioned physical characteristics, takentogether with the nature of the starting materials, the mode ofsynthesis, and elemental analyses, confirm the structures of thecompositions sought to be synthesized and patented.

The tangible embodiments of the composition aspects of the inventionpossess the inherent applied use characteristic of exerting apharmacological efiect in animals as evidenced by evaluation accordingto standard test proce- "ice dure, particularly diuretic andhypoglycemic activity. This finding indicates their usefulness in thetreatment of congestive heart failure, premenstrual syndrome (edema),edema of pregnancy, renal edema (nephrosis), cirrhosis With ascites,drug-induced edema, and diabetes mellitus.

The intermediate compositions of this invention are useful in practicingthe process aspects of the invention in the making of the principalcompositions of the invention.

The invention sought to be patented, in a principal process aspect, isdescribed as residing in the sequence of reaction including: treating a2,3 dihydro 1 phenylsulfonyl-4(1H)-quinolone with a vinyl Grignardreagent to form the corresponding 4-vinylquinolin-4-ol; condensing said4-vinylquinolin-4-ol with 2-methylcyclopentane-1,3- dione to form a6-phenylsu1fonyl-8,14-seco-6-azaestra- 1,3,5 (10),9( 1 1 )-tetraene-14,17-dione; and ring-closing said secoazaestratetraene under acidicconditions to form a 6-phenylsulfonyl-6 azaestra 1,3,5 10),8,14 pentaen-17-one.

The invention sought to be patented in a second composition aspect isdescribed as residing in the concept of a 3-methoxy-6-phenyl-sulfonyl8,14 seco 6 azaestra- 1,3,5(10),9(11)-tetraene-14-17-dione (FIGURE 1,III).

The tangible embodiments of said second composition aspect possess theaplied use characteristic of being intermediates for the preparation ofcompositions exerting pharmacological effects as evidenced by standardtest procedures.

The invention sought to be patented in a third composition aspect isdescribed as residing in the concept of a 2,3-dihydro-7 methoxy 1phenylsulfonyl 4 vinylqninolin-4-ol (FIGURE 1, H).

The tangible embodiments of said third composition aspect possess theapplied use characteristic of being intermediates for the preparation ofcompositions exerting pharmacological effects a evidenced by standardtest procedures.

The invention sought to be patented in a second process aspect isdescribed as residing in the reaction of a 2,3-dihydro-1-phenylsulfonyl-4-(1H)-quinol0ne with a vinyl Grignard reagentto form a 1,2,3,4-tetrahydro-l-phenylsulfonyl-4-vinylquinolin-4-ol.

The invention sought to be patented in a third process aspect isdescribed as residing in the condensation of a1,2,3,4-tetrahydro-1-phenyl-sulfonyl-4-vinylquinolin 4 01 with aZ-methylcyclopentane-1,3-dione to form a 6- phenylsulfonyl-8,14-seco 6azaestra 1,3,5 (10),9( 11)- tetraene-14,17-dione.

The invention sought to be patented in a fourth process aspect isdescribed as residing in the ring-closure of a 6-phenylsulfonyl-8,14-seco 6 azaestra 1,3,5 (10),9( 11)-tetraene-14,17-dione by means of acid to form a6-phenylsulfonyl-6-azaestra-1,3 ,5 l0),8,14-pentaen-17-one.

The invention sought to be patented in a fifth process aspect isdescribed as residing in the oxidative aromatization of a6-phenylsulfonyl-6-azaestra-1,3,5(l0),8-tetraene by means of lithium inliquid ammonia.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same, as follows:

Referring now to FIGURE 1, wherein the compounds are assigned Romannumerals for identification, the sequence of reactions involved in thesynthesis of a specific embodiment, namely 3-methoxy 6phenyl-sulfonyl-6- azaestra-1,3,5 (10),8,14-pentaen-17-one, isillustrated, 2,3- dihydro 7 methoxy-1-phenylsu1fonyl-4(1H)-quinol-one(I) is added to a vinyl Grignard reagent such as vinyl magnesiumchloride or bromide to form the vinyl alcohol 1,2,3,4-te-tr-ahydro 7methoxy-l-phenylsulfonyl-4- vinylquinolin-4-ol (II). This vinyl alcoholis condensed with Z-methylcyclopentane-1,3-dione using a basic catalystsuch as potassium carbonate to form the secoazestratetraene 3 methoxy 6phenylsulfonyl-8,14-seco-6-azaestral,3,5(1 ),9(1l)-tetraene-l4,17-dione(111). Treatment of this seco compound with hydrochloric acid results ina ring-closure, yielding 3-met-hoxy -6 phenylsulfonyl-6- azaestra-l,'3,5l0) ,8,l4-pentaen-l7-or1e (IV).

Compound IV, when administered to test rats in a fivehour oral diureticassay, was found to be active as a diuretic and saluretic, and topossess a favorable sodium to potassium excretion ratio. Five hoursafter administration of compound IV at a dosage of 30* mg./ kg. bystomach tube to male rats, blood samples showed a depression in bloodsugar, indicative of hypoglycemic activity.

In addition, compound IV is an intermediate useful in the synthesis ofadditional 6-azaestrane compounds. For example, and with reference toFIGURE 2, hydrogenation in the presence of the selective catalyst suchas 2% palladized strontium carbonate in benzene results in the formationof 3 methoxy 6 phenylsulfonyl-6azaestra- 1,3,5 8-tetraen-17-one. Thistetraene is reduced to the corresponding l7fi-hydroxy compound (V) bytreat ment with a reducing agent such as sodium borohydride. When eitherof the latter 6-azaestra-1,3,5(l0),8-tetraenes is subjected to theaction of lithium in liquid ammonia, in the presence or absence ofethanol, 3-methoxy-6- -azaestra-1,3,5(l0),6,8-tetraen-17-ol (V1) isproduced. This compound is l7-dihydro-6-azaequinenin-methyl ether, whichhas been converted to 6-azaequilenin by Bruckhalter and Watanabe,Abstracts of the l43-rd Meeting of the American Chemical Society, 1963,l4-A, by means of a bichromate oxidation of the 17-hydroxy group andcleavage of the 3-methoxy group by means of hydrobromic acid and aceticacid.

The above-mentioned aromatization, effected by lithium in liquidammonia, is a part of the present invention and is indeed unexpected.Lithium and liquid ammonia is a reductive reagent combination which isgenerally utilized to reduce double bond systems. A chemist familiarwith such reactions would have expected the 8(9) double bond of the6-azaest-ra-l,3,5(10),8-tetraene to have been reduced. An oxidation bymeans of this reagentcombination is thus unique and unexpected. Themechanism by which this unique reaction occurs is not yet fullyunderstood.

It is thus apparent that compound -IV, 3-methoxy-6- phenylsulfonyl 6azaestra 1,3,5(l0),8,l4-pentaen-l7- one, in addition to its inherentusefulness as a diuretic and hypoglycemic, is useful as an intermediatefor the synthesis of other 6-azaestranes, including the known.

compound 6-azaequilenin. In addition, reduction of the A and B-ringsleads to the formation of 6-aza-l9-nortestosterones.

The condensation of the vinylquinolinol II with 2-methylcyclopentanc-1,3-dione can be affected using any of a variety ofbasic catalysts. These catalysts include alkali metal carbonates such assodium and potassium carbonate, alkali metal hydoxides and alkoxidessuch as sodium and potassium hydroxide and ethoxide, and organic aminessuch as pyridine, triethylamine, and diethylamine. Ring closure of theseco compound III can be effected using acids such as hydrochloric,sulfuric, ptoluenesulfonic, or polyphosphoric acid.

As will be apparent by inspection of FIGURE 1, certain variants of thestarting materials can beemployed to perform a processes of thisinvention. It will be thus apparent that in place of the 7--methoxygroup on the quinoline ring system, there can be other lower alkoxygroups such as ethoxy, propoxy, isopropoxy, or butoxy; alkenyloxy groupssuch as allyloxy; cycloalkoxy groups such as cyclopentyloxy orcyclohexyloxy; a hydroxy group; or a hydrogen atom. Whenv such startingmaterials are employed in the processes of this invention, there will beformed 6-azaestranes bearing theco-rresponding lower alkoxy, alkenyloxy,cycloalkoxy, or hydroxy groups, or a hydrogen atom, in the 3-positionthereof. Further-more, by starting with a 5, 6, 7, or 8-polysubstitutedquinoline,

a 6-azaestrane which is correspondingly substituted in the l, 2, 3 or4-positions thereof is obtained. In the present invention, suchcompounds are the full equivalents of the 3-methoxy compounds, andprocesses utilizin gi'such starting materials are the full equivalentsof processes starting with the methoxy compounds. [I

We can utilize, in place of Z-methylcyclopentane-1,3- dione, anyZ-alkylcyclopentane-l,3-dione in the condensation with the4-vinylquinolin-4-ol. Among the alkyl groups which can thus appear onthe cyclopentane ring are ethyl, propyl, isopropyl, butyl, pentyl, andcetyl. When used in the processes of this invention, such2-alkylcyclopentanediones are converted into homologated 6- azaestraneshaving an alkyl group in the 13-position thereof. Such homologated6-azaestranes are the full equivalents of the normal 6-azaestranes, andprocesses utilizing the alkyl starting materials and intermediates arethe full equivalents of those processes utilizing the normal 6-azaestranes.

Cyclo-hexanediones can be used instead of cyclopentanediones in order toform D-homo-6-azaestranes. Such D-homo compounds and the processes forpreparing them are the full equivalents of the corresponding corn-poundshaving the cyclopentane ring and of the processes for preparing them.

In place of the phenylsulfonyl group which appears on the nitrogen atomof the various quinoline and azaestrane compounds of the invention,there can be a tolylsulfonyl group, a methylsulfonyl group, or otheraryl or lower alkylsulfonyl groups. Compounds which bear such sustituted sulfonyl groups are the equivalents of the phenyisulfonylcompounds, and'processes utilizing such substituted sulfonyl compoundsare the equivalents of those utilizing the phenylsulfonyl compounds.

Compositions of the invention having a 17-ketone function can beconverted to the corresponding 17-hydroxy compounds by reduction with anagent such as lithium aluminum hydride. These ketones can be treatedWith an organometallic reagent to introduce a group such as alkyl,alkenyl, or alkynyl into the t-POSltlOI1. They can be ketalized orthioketalized conventionally by treating with alcohols such as ethyleneglycol, trimethylene glycol, ethanedithiol, or ethanol in the presenceof an acid catalyst such as sulfuric acid or p-toluenesulfonic acid.

The 17-alcohols which result from the reduction of the 17-ketones may beesterified with any of a variety of acids by conventional means. Suchacids include acetic, propionic, phenylpropionic, cyclopentanepropionic,valeric, and caproic acids. The hydroxy group may alternatively beetherified with reagents such as methyl iodide or dimethyl sulfate- Thequinoline starting materials utilized in the present invention are oldor may be prepared according to methods known to the art. The specificcompound 2,3-dihydro- 7-methoxy-1-phenylsulfonyl-4(1I-I)-quinolone isdescribed by Braunholtz et al., J. Chem. Soc. 1957, 4166. The syntheticmethod involves the condensation of a suitably substituted aniline with,acrylic acid or an ester thereof, followed by cyclization.

The principal 6-azaestra-1,3,5:(10),8,l4-pentaene compositions can beprepared by an alternative route. A suitably substituted aniline such asm-methoxyaniline is treated with l-buten-3-yne to produce a4-anilino-l-butyne. Mannich condensation with formaldehyde anddiethylamine yields a l-diethylamino-S-anilino-2-pentyne. Hydration bymeans of aqueous mercuric sulfate and sulfuric acid results in theformation of l-diethylamino-S-m-methoxyani1inopentan-3-one. Theformation of this ketamine is accomplished by the production of anelimination product, S-m-methoxyanilino-l-penten-3-one. Either of thesecompounds, or a mixture of them, is subjected to a Michael condensationwith Z-met-hylcyclopentane-1,3-dione in the presence of a base such asmethanolic potassium hydroxide to form the trione Z-(S-m-methoxyanilino-3-oxopentyl)-2-methylcyclopentane-1,3-dione. This latter compound isthen cyclodehydrated by dissolving in a solvent such as benzenecontaining a catalytic amount of ptoluenesulfonic acid and refluxingunder a Dean-Stark trap until two equivalents of water are collected.Alternatively, the trione is treated with polyphosphoric acid at roomtemperature or slightly above until ring-closure is complete. Theproduct is 3-methoxy-6-azaestra- 1,3,5(10),8,14-pentaen-l7-one, whichcan be converted to the appropriate sulfonamide by treatment with areagent such as benzene-sulfonyl chloride, p-toluenesulfonyl chloride,or methanesulfonyl chloride.

The compositions of this invention may be formulated for pharmaceuticaluse as solid capsules, tablets, suppositories, etc. by combining themwith conventional carriers. Such conventional solid carriers includesmagnesium carbonate, magnesium stearate, talc, sugar, lactose, dextrin,pectin, starch, gelatin, tragacanth, methylcellulose and sodiumcarboxymethylcellulose. Diluents, flavoring agents, solubilizers,lubricants, suspending agents, binders, or tabletdisintegrating agentsmay be employed. Liquid preparations such as solutions, suspensions, oremulsions may also be prepared. A water-propylene glycol solution may beused for parenteral injection. An aqueous suspension suitable for oraluse can be made by utilizing natural or synthetic gums, resins,methylcellulose, or other well-known suspending agents.

The following examples set forth the best mode contemplated by theinventors of carrying out their invention.

Example1.-1,2,3,4-tefrahydr-7-methoxy-Z-phenylsulfonyl-4-vinylquin0lin-4-0l Add2,3 dihydro 7 methoxy 1 phenylsulfonyl- 4(1H)-quinolone (Braunholtz etal., J. Chem. Soc., 1957, 4166) (56 g.) in tetrahydrofuran (250 ml.)with stirring under nitrogen to vinyl magnesium chloride (49.6 g.) intetrahydrofuran (1 liter) at 0. After stirring for three hours, pourinto ice-cold ammonium chloride solution and extract with ether.Recrystallize the isolated product from ether-hexane to obtain the titlecompound (44 g.), M.P. 9094.

Example 2.-3-methoxy-6-phenylsulfony[-8,]4-sec0-6- azaestra-1,3,5 (10),9 (11 -tetraene-14,17-di0ne Reflux Z-methylcyclopentane-1,3-dione (26g.) with 1,2,3,4 tetrahydro 7 methoxy 1 phenylsulfonyl 4-vinylquinolin-4-ol (52 g.) and a pinch of potassium carbonate inmethanol 80 ml., for twenty-four hours. Cool, add to aqueous sodiumbicarbonate, and extract with ether. Wash the ether extracts withaqueous sodium bicarbonate and water, and dry. Recrystallize theisolated product from methanol containing a little tetrahydrofurantoobtain the title compound (45.5 g.), M.P. 112-116".

Example 3.3-methoxy-6-phenylsulfonyl-6-azaestra-1,3,5(10),8,14-pentzzen-17-0ne Heat to boiling3-methoxy-6-phenylsulfonyl-8,l4-seco-6-azaestra-l,3,5(10),9(11)-tetraene-14,17-dione (6 g.) in methanol (36ml.) and tetrahydrofuran (24 ml.) Add 11 N hydrochloric acid (14 ml.)slowly with swirling. Cool and filter off the resulting precipitate.Recrystallize from tetrahydrofuran-methanol to obtain the title productg.), M.P. 169-173".

Analysis.Calcd. for C H NO S: C, 68.39%; H, 5.50%; N, 4.27%; S, 7.61%.Found: C, 68.59%; H, 5.51%; N, 3.32%; S, 7.70%.

6 Example 4.3-mefhoxy-6-phenylsulf0nyl-6-azaestra- 1,3,5(10),8-tetraen-17- ne Shake 3 methoxy 6 phenylsulfonyl 6 azaestra-1,3,5(l0),8,14-pentaen-17-one (21.5 g.) with hydrogen at atmosphericpressure in benzene (530 ml.) with 2% palladized strontium carbonate (12g.) until 1,200 cc. of hydrogen are absorbed (about one hour).Recrystallize from methanol to obtain the title produce (10.35 g.), M.P.173177.

Analysis.Calcd. for C H NO S:C, 68.06%; H, 5.85%; N, 3.31%; S, 7.57%;Found: C, 67.97%; H, 5.95%; N, 3.49%; S, 7.8%.

Example 5 .3-methoxy-6-phenylsulfonyl-fi-azaestra- 1,3,5(10),8-tetraen-17-0l Suspend 3 methoxy 6 phenylsulfonyl 6 azaestra-1,3,5(10),8-tetraen-17-one (5 g.) in methanol m1.) and tetrahydrofnran(20 ml.) and treat with sodium borohydride (2 g.), When reaction hasceased, add acetic acid (10 ml.) and evaporate. Shade the residue withether and Water until complete solution is achieved, and wash theorganic layer with saturated sodium bicarbonate solution and water. Dryand evaporate. Crystallize from methanolwater (10: 1) to obtain thetitle product (4 g.), M.P. 154-157.

Example 6.3-meth0xy-6-azaestra-1,3,5(10),6,8- pen men-1 7-0l Add 3methoxy 6 phenylsulfonyl 6 azaestra- 1,3,5(10)8-tetraen-17-ol (1 g.) intetrahydrofuran (50 ml.) to distilled liquid ammonia (100 ml.). Then addlithium metal (0.03 mg., 2 atomic equivalents) and stir vigorously untilall the lithium has dissolved. Add dilute acetic acid (50% W./v.) andthen an excess of water. Extract with ether and then extract with theether layers with 10% hydrochloric acid. Make basic the aqueous acidextracts and extract again with ether. Wash the ether extracts withwater, saturated sodium bicarbonate solution, and water, dry, andevaporate to obtain the title product (200 mg.). Ultraviolet absorption:k 234, 326, 340 m (6 54,200, 4,700, 4,700). Infrared absorption peak at3,165 cmf We claim:

1. 3 methoxy 6 phenylsulfonyl 6 azaestra- 1,3,5 10) ,8,14-pentaen-17-one.

2. 3 methoxy 6 phenylsulfonyl 8,14 seco- 6azaestra-1,3,5(10),9(11)-tetraene-14,17-dione.

3. 1,2,3,4 tetrahydro 7 methoxy 1 phenylsulfonyl- 4-vinylquinolin-4-ol.

4. A process for the preparation of a 6-azaestra- 1,3,5(10),6,8-pentaene comprising for oxidative aromatization of a6-iphenylsulfonyl-6-azaestra-1,3,5(10),8-tetraone by means of lithium inliquid ammonia.

References Cited UNITED STATES PATENTS 2,796,420 6/1957' Weisenborn260-287 2,921,964 l/1960 Ramsden 260289 X 3,219,668 11/1965 Brown et a1.260-289 OTHER REFERENCES Huisman et al.: Rec. Trav. Chim., volume 82,page 898 to 900 (1963).

ALEX MAZEL, Primary Examiner. D. G. DAUS, Assistant Examiner.

1. 3 - METHOXY - 6 - PHENYLSULFONYL -6 -AZAESTRA1,3,5(10),8,14-PENTAEN-17-ONE.
 3. 1,2,3,4-TETRAHYDRO - 7 -METHOXY - 1 - PHENYLSULFONYL4-VINYLQUINOLIN-4-OL.